The two major theories that attempt to explain the increase in coronary blood flow (CBF) that follows release of a brief coronary occlusion are the vasodilator metabolite and the myogenic tone theories. We hypothesized that if the heart muscle were already ischemic, a brief coronary occlusion should produce a little further increase in metabolites and little or no reactive hyperemic increase in CBF. We previously found that arginine-8-vasopressin (AVP) and neuropeptide tyrosine (NPY) caused coronary vasoconstriction severe enough to produce myocardial ischemia. Thus we used the same doses of AVP (n=5) or NPY (n=6) in the same experimental model, (chloralose-anesthetized, open chest dogs) and found the same decreases in CBF. We compared the reactive hyperemic increase in CBF after release of 15 sec coronary occlusions before vs after one of the peptides had reduced CBF by 41-48%. Peak reactive hyperemic CBF was reduced by only 18-22 % (p-N.S.) after peptide-induced vasoconstriction that was severe enough to produce myocardial ischemia. These results are difficult to explain by the vasodilator metabolite theory because the ischemia existing before the coronary occlusion should have stimulated production of vasodilator metabolites. If the virtually normal vasodilator reserve manifested during reactive hyperemia had been available to the heart during peptide-induced vasoconstriction, then ischemia might have been prevented. These findings suggest an additional, non-metabolic stimulus to ractive hyperemia. We measured distal coronary branch pressure (DCP) to assess indirectly the myogenic stimulus for coronary arterial tone. DCP was not altered by peptide-induced vasoconstriction, and occlusion reduced DCP to similar values before vs during peptide infusion. The same decrease in DCP during occlusion should provide the same decrease in myogenic tone as a stimulus for reactive hyperemia with or without vasoconstriction. Thus, these data support an important role for changes in myogenic tone to regulate the reactive hyperemic increase in CBF.